There are currently no drugs available that prevent the nerve cell death associated with the majority of age-related disorders of the CNS. There are a number of reasons for this but probably the most important is that multiple factors contribute to the nerve cell death such that targeting a single pathway is unlikely to be successful. One example of this problem is ischemic stroke which is the leading cause of adult disability and the third leading cause of death in the US (Véronique, et al., Circulation. (2011) 123 (4), e18-e209). Worldwide, approximately 5 million people die each year of stroke and the mortality rates are estimated to double by the year 2020 (Donnan, et al., The Lancet. (2008), 371 (9624), 1612-1623). The nerve cell death associated with cerebral ischemia is due to multiple factors resulting from the lack of oxygen to support respiration and ATP synthesis, acidosis due to the buildup of the glycolytic product lactic acid, the loss of neurotrophic support, multiple metabolic stresses and inflammation (Lipton, Physiol. Rev. (1999) 79, 1431-1568; and Pandya, et al., Cent. Nerv. Syst. Agents. Med. Chem. (2011) Apr 27, PMID:21521165). While the focus of current drug discovery paradigms is on the development of high affinity, single target ligands, it is unlikely that a drug directed against a single molecular target will be effective in treating the nerve cell death associated with conditions such as stroke because of the multitude of insults that contribute to the cell's demise. This conclusion is supported by the failure of the single, high affinity target approach to drug development to identify treatments for stroke. Indeed, the only FDA-approved treatment to date is recombinant tissue-type plasminogen activator (rt-PA) (Green, et al., Drug Discov. Today. (2006) 11, 681-693), which is a vascular agent. An alternative approach is to identify small molecules that have multiple biological activities relevant to the maintenance of neurological function.
The flavonal Fisetin has been found to be an orally active, novel neuroprotective and cognition-enhancing molecule (Maher, Genes. Nutr. (2009), Sep 10, PMID:19756810). Fisetin not only has direct antioxidant activity but it can also increase the intracellular levels of glutathione, the major intracellular antioxidant, via the activation of transcription factors such as Nrf25. Fisetin can also maintain mitochondrial function in the presence of oxidative stress. In addition, it has anti-inflammatory activity against immune cells and inhibits the activity of 5-lipoxygenase, thereby reducing the production of lipid peroxides and their pro-inflammatory by-products (Maher, Genes. Nutr. (2009), supra). This wide range of actions suggests that Fisetin has the ability to reduce the loss of neurological function associated with multiple disorders, including stroke.
Although Fisetin has been shown to be effective in the rabbit small clot embolism model of stroke (Maher, et al., Brain Research. (2007) 1173, 117-125), its relatively high EC50 in cell based assays (2-5 μM) and also low lipophilicity (CLogP 1.24), high tPSA (107 Å), more hydrogen bond donors (HBD=5) and poor bioavailability (Shia, et al., J. Agric. Food Chem. (2009) 57 (1), 83-89) suggest that there is room for medicinal chemical improvement if Fisetin is to be used therapeutically for treating neurological disorders such as stroke. However, given its ability to activate multiple target pathways related to neuroprotection, screening for improvements is significantly more complicated than with the current classical approach to the development of a single target drug. The present invention is based in part, on the use of a multi-tiered approach to screening that has facilitated the identification of Fisetin derivatives with significantly enhanced neuroprotective activity in an in vitro ischemia model while at the same time maintaining other key actions including anti-inflammatory and neurotrophic activity as well as the ability to maintain glutathione under conditions of oxidative stress.